Evaluation of RC48-ADC in combination with PRaG regimen: An open-label, prospective, multicentre study assessing efficacy and safety for advanced refractory HER2-expressing solid tumors (PRaG3.0 Study Protocol)

IntroductionCombining antibody-drug conjugates (ADCs) with radioimmunotherapy is a feasible and highly promising approach for treating HER2-positive patients, offering a potential paradigm for pan-cancer therapy. ADCs have demonstrated significant efficacy in cancers expressing human epidermal growth factor receptor 2 (HER2), independent of the tumors tissue of origin. Preclinical studies suggest that ADCs not only induce immunogenic cell death but also selectively enhance tumor radiosensitivity, providing a strong rationale for their integration with immunotherapy and radiotherapy. A combination regimen (PRaG) including hypofractionated radiotherapy (HFRT) alongside a PD-1 inhibitor and GM-CSF leverages HFRT to trigger tumor antigen release, GM-CSF to stimulate the proliferation and activation of antigen-presenting cells, and PD-1 inhibitors to relieve suppression of CD8+ T cells. The trial reported an objective response rate (ORR) of 16.7%, with three patients achieving complete remission. Building upon these findings, a next-generation regimen--disitamab vedotin (RC48) ADC combined with PRaG regimen (termed PRaG3.0)--may further amplify synergistic antitumor effects in HER2-expressing cancers. This precise combination therapy offers an innovative and exploratory approach for treating patients with HER2-positive or HER2-low tumors across various tissue types, potentially addressing the unique challenges associated with HER2 expression heterogeneity. ObjectiveThis study aims to investigate the effectiveness and safety of RC48-ADC combined with PRaG regimen for HER2-expressing advanced solid tumors. Methods and analysisThis study is a prospective, single-arm, open-label, multi-center clinical trial designed as a basket study. Enrolled patients with confirmed HER2-expressing solid tumors (IHC 3+, 2+, or 1+) that had progressed after standard treatment or were intolerant to it were divided into three cohorts: pancreatic cancer, gynecological tumors, and others. Patients received RC48 (2 mg/kg) via intravenous injection on day 1, followed by subcutaneous GM-CSF at 200 {micro}g from days 3 to 7 and interleukin-2 (IL-2) at 2 million IU from days 8 to 12. Radiotherapy was initiated on day 3, targeting one lesion with hypofractionated radiotherapy (2-3 fractions of 5 or 8 Gy). PD-1/PD-L1 antibodies were administered within one week after completing radiotherapy. Treatment was repeated every three weeks, and if there were no target lesions, radiotherapy could be discontinued, with RC48 given for at least six cycles. After achieving a complete tumor response, maintenance therapy with PD-1/PD-L1 antibodies continued until disease progression or intolerable toxicity occurred. The primary endpoint was the objective response rate (ORR). Ethics and disseminationThe study protocol received approval from the Ethics Committee of the Second Affiliated Hospital of Soochow University (JD-LK-2022-121-02), as well as from all other participating hospitals. The clinical trial registration number is NCT05115500 and registration Date date is November 4, 2021.